Functionally, loss of SMAD4 abrogates canonical TGF-β–mediated growth inhibition and cell-cycle arrest, shifting the net effect of the TGF-β axis from tumor suppression toward tumor-promoting processes such as EMT (Epithelial–Mesenchymal Transition), invasion, and stromal remodeling—mechanisms that plausibly underpin the association between SMAD4 loss and worse overall survival and therapeutic resistance in CRC patients [37]. Here, SMAD4 is linked to neoplasm.